Members of transforming growth factor (TGF-beta) potently inhibit proliferation of many types of cells. Mutations in TGF-beta signal transduction pathway leads to development of polyposis and colon cancer. TGF-beta and retinoic acid, a lipophilic molecule that binds and activates nuclear transcription factors such as retinoic acid receptor (RAR), inhibit growth of certain colon cancer cells. Through a functional expression cloning strategy involving a retroviral cDNA library, we isolated a group of cDNAs whose over-expression causes resistance to TGF-beta mediated growth inhibition. This group cDNAs include the dominant negative form of the retinoid X receptor and a novel cDNA, clone #6. Our preliminary results show that TGF-beta and retinoic acid synergistically inhibit proliferation of mink lung epithelial cells. Ibn this proposal, first, we seek to determine if TGF-beta and RA synergistically inhibit growth of various colon cancer cells. We will further investigate how TGF-beta signal transducer Smads and retinoic acid receptor cross- talk to inhibit cell growth. Second, in a DNA microarray analysis searching for TGF-beta inducible genes, we identified a transcription factor Dec1/Stra13. We will elucidate the function of Dec1/Strat13 in integrating the TGF-beta and retinoic acid signaling. Finally, we will investigate the function of clone #6 in TGF-beta and retinoic acid signaling pathways in colon cells. Results from these studies will likely shed light on development of novel therapeutic interventions by combining the activators for each of these pathways.